N1-(4-(6-Chloropyrimidin-4-yloxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamide → N1-(3-Fluoro-4-(6-(methylamino)pyrimidin-4-yloxy)phenyl)-N3-(4-fluorophenyl)malonamide

HRID 1670191Notes

Reaction equation

HRID 1670191 reaction equation
Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])=[CH:11][C:10]=2[F:29])[CH:3]=1.[CH3:30][NH2:31].C1COCC1>CCCCO>[F:29][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:28])[CH2:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:19])[CH:13]=[CH:14][C:9]=1[O:8][C:4]1[CH:3]=[C:2]([NH:31][CH3:30])[N:7]=[CH:6][N:5]=1

Participants

4

Reactant 2

HCID 59852939N1-(4-(6-Chloropyrimidin-4-yloxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamideHCID 66615946Methylamine tetrahydrofuran

Product 1

HCID 59852909N1-(3-Fluoro-4-(6-(methylamino)pyrimidin-4-yloxy)phenyl)-N3-(4-fluorophenyl)malonamideYield 34%

Reagents, catalysts & solvents 1

HCID 2631-ButanolSolvent

Procedure

A solution of N1-(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamide (100 mg, 0.42 mmol, Example 4) in n-BuOH (3 mL) was treated with 2 M methylamine/THF (0.2 mL) and heated in a screw cap vial at 80° C. for 12 h. The mixture was concentrated and the residue purified by preparative HPLC using a gradient of MeOH—H2O containing 0.1% TFA. The fraction containing the product was lyophilized to give the title compound as a pale yellow solid (60 mg, 34%). 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 10.36 (br s, 2H), 8.19 (br s, 1H), 7.76 (d, 1H, J=12.1 Hz), 7.64-7.62 (m, 2H), 7.36-7.27 (m, 2H), 7.15 (dd, 2H, J=8.8, 8.8 Hz), 5.95 (br s, 1H), 3.49 (s, 2H), 2.80 (s, 3H); MS (ESI+) m/z 414.16 (M+H)+.

Workup

  1. temperatureheated in a screw
  2. customcap vial at 80° C. for 12 h
  3. concentrationThe mixture was concentrated
  4. customthe residue purified by preparative HPLC
  5. additionThe fraction containing the product

Sources & evidence

ORD record
ord-a890413e034d4550aa0efd7cd6b6c97f
Source dataset
uspto-grants-2011_08
Patent number
US07989477B2

Reaction notes

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